Vascular embolization material

ABSTRACT

This invention provides an embolization material used for blocking a blood vessel in vivo for stopping the blood flow. The most suitable embolization material has a water swelling ratio of 30% or more, is degradable in a phosphate buffered saline, is formed as virtually spherical particles, and is preferably composed of a water insoluble poly(ethylene glycol) copolymer, wherein when the film formed from said polymer is saturated with water, it has an elastic modulus in tension of 1500 MPa or less. The embolization material of this invention can reliably block a blood vessel at an intended site without causing cohesion or clogging in a catheter or in the blood vessel at other than the intended site. Thereafter, the blocked site concerned can be liberated from the embolized state by degradation, and the degraded components can be metabolized or excreted outside the body.

TECHNICAL FIELD

The present invention relates to an embolization material and anembolization method used for blocking a blood vessel to stop the bloodflow in vivo.

BACKGROUND ART

It is known that if an embolization material is injected into a bloodvessel prior to an incision for a surgical operation with an intensionto minimize hemorrhage, hemostasis can be ensured reliably and quickly.Furthermore, aside from the purpose of preventing hemorrhage, known isthe arterial embolization intended for hemostasis to stop the supply ofnutrition to a tumor incapable of being excised. Moreover, known is thechemical embolization therapy in which an anticancer drug and anembolization material are administered in combination to keep theanticancer drug concentration high in a tumor.

Thanks to the development of catheters and their operation methods, anadequate embolization material can now be selectively accurately fedinto the site to be blocked. Conventional intravascular embolizationmaterials as used in these practices include liquid materials and solidmaterials.

Known liquid materials include organic solvents per se, and solutionsobtained by dissolving monomers and polymers into organic solvents.Typical examples include the following:

-   Ethanol described in M. Koda, et al., Cancer, 2001, Vol. 92 (6),    pages 1516-1524-   Cyanoacrylate described in the n-BCA Trial Investigators, American    Journal of Neuroradiology, 2002, Vol. 23 (5), pages 748-755 Solution    of ethylene-vinyl alcohol copolymer described in JP2000-502321T2    (pages 1-20)

These liquid materials have an advantage that they can virtuallyperfectly fill blood vessels at intended sites irrespectively of bloodvessel diameters, blood vessel bifurcations and blood vessel forms.

However, they have a problem that since they are liquids with lowviscosities, it is difficult to control their concentrations at injectedsites. Furthermore, they have such problems that they flow to theperipheries of distal portions and that they leak into veins. Stillfurthermore, since an organic solvent such as dimethyl sulfoxide isused, any influence on the bodys is feared.

On the other hand, the solid materials include metallic materials,organic synthetic materials and materials derived from naturalmaterials. Typical examples of metallic materials include the Ni—Ticoils and stents described in M. Anthony, et al., American Journal ofNeuroradiology, 2000, Vol. 21 (8), pages 1523-1531.

Known typical examples of the organic synthetic materials include thefollowing:

-   Poly(vinyl alcohol) particles described in C. P. Dardeyn, American    Journal of Neuroradiology, 1995, Vol. 16, pages 1335-1343-   Sodium acrylate-vinyl alcohol copolymer particles described in    JP6-56676A (pages 1-8)-   Gelatin-covered crosslinked polyacrylate particles described in U.S.    Pat. No. 5,635,215 and JP6-508139T2-   Ethylene-vinyl alcohol copolymerfoam described in JP2000-502321T2    (pages 1-20), JP2000-505045T2 (pages 1-25) and JP2000-506514T2    (pages 1-25).

Known materials derived from natural materials include the following:

-   Crosslinked starch particles described in T. Kumada, et al.,    Nihon-Rinsho (=Japanese Clinical Medicine), 2001, 59, Suppl., 6,    pages 539-544, crosslinked gelatin particles described in    JP60-20934A (pages 1-4) and JP60-222046A (pages 1-5), and alginic    acidgel described in U.S. Pat. No. 3,103,368 (pages 1-5) and    JP6-329542A (pages 1-4).

These solid materials have advantages that they are easy to handle whenthey are indwelled or injected and that they are excellent in operationconvenience, but have a problem that they cannot respond to complicatedforms of blood vessels.

Especially the conventional embolization materials formed as particleshave the following problems.

-   (1) It can happen that they cannot block blood vessels at intended    sites.-   (2) It can happen that they cohere together in catheters, to clog    the catheters.-   (3) It can happen that they cohere together in normal blood vessels    on the way to the intended blood vessels and do not reach the    diseased parts.-   (4) It can happen that they cannot perfectly stop the blood flow    though they can reduce it.-   (5) In the case where a material non-degradable in vivo is used, it    remains in vivo for a long period of time without being degraded or    absorbed though it is not necessary to permanently stop the blood    flow.

Known examples of biodegradable or bioabsorbable materials used includethe following:

-   Poly(lactic acid) particles described in C. Witte, et al., European    Journal of Pharmaceutics and Biopharmaceutics, 2001, Vol. 51, Nos.    171-181, gelatin sponge described in International Publication No.    98/03203, and crosslinked starch particles described in the    aforesaid document of T. Kumada, et al.

These materials have a feature that they are hydrolyzed or degraded byenzyme in vivo. However, these materials have the above-mentionedproblems (1) through (4). Furthermore, since starch particles arehydrolyzed by amylase in blood in a time period in the order of minutes,they are inadequate for long-term hemostasis and embolization. Moreover,JP5-969A discloses an embolization material composed of a copolymerobtained by copolymerizing biodegradable poly(lactic acid) or lacticacid and glycolic acid and containing a specific drug. This also has theabove-mentioned problems (1) through (4).

JP5-17245B discloses that a drug is mixed with a base polymer such aspoly(lactic acid) (hereinafter called PLA)-poly(ethylene glycol)(hereinafter called PEG), PLA-PEG-PLA or {poly(lactic acid/glycolicacid) copolymer} (hereinafter called PLGA) -PEG-PLGA as a blockcopolymer consisting of PEG, PLA or PLGA, for being slowly released, andthat it is used for medicinal and pharmaceutical applications. However,the document does not teach the use as an embolization material.

DISCLOSURE OF THE INVENTION

This invention has the following constitutions.

-   1. An embolization material that has a water swelling ratio of 30%    or more and is formed as particles containing a synthetic polymer,    being degradable in a phosphate buffered saline of 37° C.-   2. An embolization material, according to item 1, wherein the    synthetic polymer is a water insoluble poly(ethylene glycol)    copolymer.-   3. An embolization material, according to item 1 or 2, which has a    water swelling ratio of 100% or more.-   4. An embolization material, according to any one of items 1 through    3, which is formed as virtually spherical particles at 37° C.-   5. An embolization material, according to any one of items 1 through    4, which has a particle size distribution width in a range of    average particle size ±100 micrometer-   6. An embolization material, according to any one of items 1 through    5, wherein the weight of it remaining after it is immersed in a    phosphate buffered saline of 37° C. for 28 days is 80% or less of    the weight of it not yet immersed.-   7. An embolization material that has a water swelling ratio of 30%    or more and is degradable in a phosphate buffered saline of 37° C.,    being formed as virtually spherical particles with an average    particle size of 50 micrometer or more.-   8. An embolization material, according to item 7, which contains a    water insoluble poly(ethylene glycol) copolymer.-   9. An embolization material, according to item 7 or 8, which has a    water swelling ratio of 100% or more.-   10. An embolization material, according to any one of items 7    through 9, wherein the weight of it remaining after it is immersed    in a phosphate buffered saline of 37° C. for 28 days is 80% or less    of the weight of it not yet immersed.-   11. An embolization material that is composed of a water insoluble    polymer, in which when the film formed from the water insoluble    polymer is saturated with water, it has an elastic modulus in    tension of 1500 MPa or less.-   12. An embolization material, according to item 11, wherein the film    saturated with water has an elastic modulus in tension of 4 to 400    MPa.-   13. An embolization material, according to item 11 or 12, wherein    the elastic modulus in tension of the film saturated with water is    60% or less of the elastic modulus in tension of the film in the dry    state.-   14. An embolization material, according to any one of items 11    through 13, wherein the film saturated with water has a tensile    elongation of 100% or more.-   15. An embolization material, according to any one of items 11    through 14, which has a water swelling ratio of 100% or more.-   16. An embolization material, according to any one of items 11    through 15, wherein the weight of the water insoluble polymer    remaining after it is immersed in a phosphate buffered saline of    37° C. for 28 hours is 80% or less of the weight of it not yet    immersed.-   17. An embolization material, according to any one of items 11    through 16, wherein the water insoluble polymer is a block copolymer    with a structure in which the structure of a biodegradable polymer    and the structure of a water soluble polymer are chemically bonded    to each other.-   18. An embolization material, according to any one of items 1    through 16, wherein the water insoluble polymer is a poly(ethylene    glycol) copolymer.-   19. An embolization material comprising a water insoluble    poly(ethylene glycol) copolymer.-   20. An embolization material, according to item 19, wherein the    water insoluble poly(ethylene glycol) copolymer is a copolymer with    a structure in which a poly(ethylene glycol) derivative and a    biodegradable polymer are chemically bonded to each other.-   21. An embolization material, according to item 19, wherein the    water insoluble poly(ethylene glycol) copolymer is a copolymer with    a structure in which a biodegradable polymer is chemically bonded to    the hydroxyl groups of a poly(ethylene glycol) derivative.-   22. An embolization material, according to item 20 or 21, wherein    the water insoluble poly(ethylene glycol) copolymer is a mixture    consisting of a poly(ethylene glycol) copolymer containing a polymer    synthesized from L-lactic acid or L-lactide as the structure of the    biodegradable polymer and a poly(ethylene glycol) copolymer    containing a polymer synthesized from D-lactic acid or D-lactide as    the structure of the biodegradable polymer.-   23. An embolization material, according to any one of items 20    through 22, wherein the poly(ethylene glycol) derivative as a    component of the water insoluble poly(ethylene glycol) polymer has a    structure in which a compound having three or more hydroxyl groups    and poly(ethylene glycol) are chemically bonded to each other.-   24. An embolization material, according to any one of items 20    through 23, wherein the water insoluble poly(ethylene glycol)    copolymer has a weight average molecular weight of 3000 to 100000,    and the structure of the poly(ethylene glycol) derivative existing    in the poly(ethylene glycol) copolymer has a weight average    molecular weight of 2000 to 50000.-   25. An embolization material, according to any one of items 19    through 24, which has a water swelling ratio of 100% or more.-   26. An embolization material, according to any one of items 19    through 25, which is formed as particles at 37° C.-   27. An embolization material, according to item 26, which has an    average particle size of 50 to 2000 micrometer.-   28. An embolization material, according to item 26 or 27, which has    a particle size distribution width in a range of average particle    size ±100 micrometer.-   29. An embolization material, according to any one of items 26    through 28, which is formed as virtually spherical particles at 37°    C.-   30. An embolization material, according to any one of items 19    through 29, wherein the weight of it remaining after it is immersed    in a phosphate buffered saline of 37° C. for 28 days is 80 wt % or    less of the weight of it not yet immersed.-   31. An embolization material, according to any one of items 19    through 30, which can be swollen with at least any one of purified    water, physiologic saline and water soluble X-ray contrast medium.-   32. An embolization material, according to any one of items 19    through 31, which further holds a water soluble X-ray contrast    medium in it.-   33. An embolization material, according to any one of items 19    through 32, which has flexibility of being deformed in response to    the form of the blood vessel at the time of embolization for    allowing the blood flow to be stopped.-   34. An embolization material, that contains a synthetic polymer, has    a water swelling ratio of 30% or more, is degradable in a phosphate    buffered saline of 37° C., and is formed as virtually spherical    particles with an average particle size of 50 micrometer or more,    wherein the synthetic polymer is a water insoluble poly(ethylene    glycol) copolymer and the film formed from the synthetic polymer and    saturated with water has an elastic modulus in tension of 1500 MPa    or less.-   35. An embolizing agent, having the embolization material as set    forth in any one of items 1 through 34 dispersed in a physiologic    saline.-   36. An embolization method, comprising the steps of inserting a    catheter percutaneously into a blood vessel of an body, to let its    tip reach the site to be blocked, and injecting a solution    containing the embolization material as set forth in any one of    items 1 through 34 through the catheter into the site to be blocked,    for blocking the blood vessel.

THE BEST MODES FOR CARRYING OUT THE INVENTION

The embolization material and the embolizing agent of this invention aretherapeutic materials that are intended to easily reach the intendedportion of a blood vessel and to be deformed in response to the bloodvessel form near a tumor, lesion or bleeding site to positively blockthe blood vessel for stopping the blood flow without injuring the bloodvessel, and is intended to be degraded for vanishing after the purposehas been achieved. Materials capable of satisfying these intensions havebeen examined intensively, and as a result, modes preferred in view offlexibility, degradability, form (particles, virtually spherical form,particle size, particle size distribution width) and compositions of rawpolymers have been found.

It is preferred that the embolization material of this invention isflexible. As a flexible material, a material capable of absorbing waterand swelling can be preferably used. A material being capable ofabsorbing water and swelling means that the material can absorb waterand swell because of the absorbed water, to increase in weight andvolume. If the material is formed as particles, the swelling ratio ofthe material owing to water can be used as a flexibility indicator. Evenif the material is formed as particles or any other form, the compoundor composition constituting the material can be formed into a film, andthe water content or elastic modulus of the film saturated with watercan be used as a flexibility indicator.

In this invention, in the case where the embolization material is formedas particles, the swelling ratio owing to water can be measured asdescribed below.

If the diameter of a particle swollen after immersion in purified waterfor more than 12 hours is R, and that in the dry state is R0, the waterswelling ratio (%) can be calculated from (R³−R₀ ³)/R₀ ³×100. (R³ meansthe third power of R, and R₀ ³, the third power of R₀.) A micrometer canbe used to observe the changes of particle sizes, and the mean value ofvolume changes of 10 particles can be used as the water swelling ratio.In the above, the dry state refers to a state reached by drying invacuum for more than 12 hours subsequently to preliminary drying in air.In the examples of this invention, “an ultra depth shape measuringmicroscope, VK-8500” produced by Keyence was used for directly observingthe particle sizes.

In view of the flexibility of being deformed in response to the innerform of a blood vessel without injuring it, it is preferred that thewater swelling ratio is 30% or more. Especially preferred is 100% ormore. In the case where the water swelling ratio is too small, evenparticles smaller than the inner diameter of a microcatheter cannot passthrough the microcatheter.

Furthermore, in this invention, the water content can be measured usinga cast film as described below.

At first, the compound or composition constituting embolizationparticles or an embolization material is dissolved into an organicsolvent capable of dissolving it, to obtain a solution. The solution isdeveloped on a plate with an inner diameter of 85 micrometer and driedto obtain an about 30 micrometer thick film.

The water content obtained by measuring the weight W of the filmsaturated with water after immersion in purified water for more than 12hours and the weight W₀ of the film in the dry state for calculating thedifference between the weights can also be used as an indicator of waterswelling capability. It can be calculated from the following formula:Water content (%)=(W−W ₀)/W ₀×100

In view of the flexibility of being deformed in response to the form ofa blood vessel without injuring the blood vessel, it is preferred thatthe water content of the film is 30% or more. Especially preferred is100% or more. In the case where the water content of the film saturatedwith water is too low, even particles smaller than the inner diameter ofa microcatheter is unlikely to pass through the microcatheter.

Moreover, in this invention, the elastic modulus values and tensileelongation values of the film saturated with water and the film in thedry state can be measured as described below. The film can be producedaccording to the above-mentioned method.

-   Test environment: Laboratory temperature 23° C., laboratory humidity    50%-   Form of specimen: Strip (7.5 mm×80 mm)-   Inter-chuck distance: 20 mm-   Stress rate: 10 mm/min    Except these measuring conditions, the measurement was made    according to the method described in JIS K 7161 (1994). Meanwhile,    in the examples of this invention, “RTM-100” produced by Orientec    Corporation was used as the tensile tester.

In view of the flexibility of being deformed in response to the form ofa blood vessel without injuring the blood vessel, it is preferred thatthe elastic modulus in tension of the film saturated with water is 1500MPa or less. It is more preferred that the elastic modulus in tension isfrom 4 to 400 MPa. It is especially preferred that the elastic modulusin tension of the film saturated with water is 60% or less of theelastic modulus in tension of the film in the dry state. In addition,for acquiring such deformation resistance that the material is notbroken even at a high pressure acting during the injection from asyringe into a blood vessel, it is especially preferred that the filmsaturated with water has a tensile elongation of 100% or more.

It is preferred that the embolization material of this invention isdegradable in vivo. An indicator of the degradability in vivo can be theweight loss of particles in a phosphate buffered saline of 37° C. It ispreferred that the weight of the embolization material of this inventionremaining after it is immersed in a phosphate buffered saline of 37° C.for 28 days is 80% or less of the weight of it not yet immersed. It ismore preferred that the weight of it remaining after immersion for 28days is 50% or less of the weight of it not yet immersed. The phosphatebuffered solution can be obtained, for example, by diluting thephosphate buffered saline (pH 7.4, 10-fold concentrated) produced byNacalai Tesque, Inc. to 10 times. In the examples of this invention,about 200 mg (dry weight W0) of an embolization material was dispersedinto 10 mL of the phosphate buffered saline in a test tube, and the testtube was rotated at a rate of one revolution per 2 seconds by a rotator,for shaking the content of the test tube in an environment of 37° C.After lapse of a predetermined period of time, the water solublecomponent was removed using a micropipette, and subsequently the washingof the residue with purified water and the removal of the water solublecomponent were repeated three times. The residue was dried in air anddried in vacuum, and its weight W was measured.

It is preferred that the embolization material of this invention isformed as particles at 37° C., especially as virtually sphericalparticles. It is more preferred that the average particle size and theparticle side distribution width are in respective specific ranges asdescribed later.

An embolization material formed as particles can be produced, forexample, by the following method.

The polymer (the detail is described later) used as a raw material ofthe embolization material is dissolved into, for example,dichloromethane, chloroform, ethyl acetate, isopropyl ether or the like,to obtain a solution. It is dispersed into a water phase containing asurfactant, protective colloid agent or the like, and a publicly knownmethod of drying in an O/W emulsion or W/O emulsion, a similar method,spray-drying method, or the like is used to obtain an embolizationmaterial formed as particles.

As another method, the raw material of the embolization material isdissolved into a water miscible organic solvent such the organic solventused as a component of the solution is substituted by water or watercontaining a surfactant, to obtain an embolization material formed asparticles. The surfactant or protective colloid agent used in this caseis not especially limited, if it can form a stable oil/water emulsion.Examples of the materials include anionic surfactants (sodium oleate,sodium stearate, sodium lauryl sulfate, desoxycholic acid, etc.),nonionic surfactants (polyoxyethylene sorbitan fatty acid ester,polyoxyethylene castor oil derivative, etc.), poly(vinyl alcohol),polyvinylpyrrolidone, carboxymethyl cellulose, lecithin, gelatin, etc.Plural compounds can also be selected from among them for use incombination.

Furthermore, as the surfactant or protective colloid agent, a watersoluble A-B type block copolymer in which A denotes a biodegradablepolymer while B denotes methoxy polypoly(ethylene glycol) can bepreferably used. Among the surfactants and protective colloid agents,poly(vinyl alcohol), carboxymethyl cellulose and gelatin can beespecially preferably used.

A preferred concentration of the surfactant or protective colloid agentcan be selected in a range from 0.01 to 20 wt % as an aqueous solution.A more preferred range is from 0.05 to 10 wt %.

The particles produced like this are generally virtually sphericalparticles, but some amorphous particles may be contained. For thepurpose of removing such particles or for the purpose of classification,plural sieves with adequate mesh sizes can be used to obtain particleswith an intended average particle size and an intended particle sizedistribution. In this case, the particles to be sieved can be either dryparticles or wet particles immersed in water.

In the case where the embolization material of this invention is formedas particles, the particle size and particle size distribution can bemeasured by an electric resistance method or light scattering method.

As a means for using the electric resistance method, Coulter MultisizerII or III produced by Scientific Instruments can be used. As a means forusing the light scattering method, “MICROTRAC HRA-X100” produced byLeeds and Northrup can be used.

In the former case, since measurement is made in a physiologic saline,measurement can be made in an environment close to the inside of a bloodvessel. In the latter case, measurement is made in purified water. Ineither case, the value of volume average is employed as the averageparticle size.

It is preferred that the average particle size of the embolizationmaterial of this invention is 50 micrometer or more. More preferred is60 micrometer or more. On the other hand, 2000 micrometer or less ispreferred. More preferred is 1500 micrometer or less. In the case wherethe average particle size is too small, a site other than the intendedblood vessel may be blocked. Considering the diameter of the actualblood vessel to be blocked, it is preferred that the average particlesize is in a range between said lower limit and said upper limit. It isfurther preferred that the average particle size is selected as requiredin response to the diameter of the blood vessel to be blocked.

For the purpose of realizing more reliable blocking, it is preferredthat the particle size of the embolization material of this invention isuniform. For example, it is preferred that the particle sizedistribution width is in a range of average particle size ±100micrometer. More preferred is a range of average particle size ±50mictometer. Meanwhile, the particle size distribution width refers to aparticle size range from D1 to D99 for average particle size D50 interms of volume.

It is preferred that the embolization material of this invention isformed as virtually spherical particles, since virtually sphericalparticles allow perfect blocking in a blood vessel.

It is preferred that the embolization material of this inventioncontains a synthetic polymer artificially synthesized. Furthermore, itis preferred that the embolization material is mainly composed of asynthetic polymer.

Examples of the synthetic polymer in this invention include a waterinsoluble poly(ethylene glycol) copolymer and non-crosslinkedpoly(propylene fumarate) synthesized from fumaric acid and propyleneglycol.

At first, the water insoluble poly(ethylene glycol) copolymer isdescribed.

A water insoluble poly(ethylene glycol) copolymer is poly(ethyleneglycol), a poly(ethylene glycol) derivative such as methoxypoly(ethylene glycol) or multi-branched poly(ethylene glycol), a blockcopolymer obtained using a poly(ethylene glycol) derivative as a rawmaterial component, or a stereo complex forming block copolymer in whichtwo or more block copolymers physically interact with each other, etc.,and is insoluble in water. A copolymer in which physical interactionwith poly(ethylene glycol) or any of its derivatives causesinsolubilization in water, such as polyrotaxane formed from cyclodextrinand poly(ethylene glycol) can also be used. Multi-branched poly(ethyleneglycol) is a compound having a structure in which a compound with threeor more hydroxyl groups such as glycerol, polyglycerol, pentaerythritolor polypentaerythritol and poly(ethylene glycol) are chemically bondedto each other. Particularly, tri-branched “Sunbright GL,” tetra-branched“Sunbright PTE” and octa-branched “Sunbright HGEO (respectively producedby NOF Corp. ) can be preferably used. Originally poly(ethylene glycol)is soluble in water. So, in this specification, the water insolublepoly(ethylene glycol) copolymer means that a structure other than thestructure of poly(ethylene glycol) contributes to ensure that the entirepoly(ethylene glycol) polymer containing the structure of poly(ethyleneglycol) is not dissolved into water. Particularly it means that whensaid material is immersed in water at 23° C., it is not dissolved intowater within 30 minutes.

The molecular weight of the poly(ethylene glycol) structure portioncontained in the poly(ethylene glycol) copolymer is not especiallylimited, but a poly(ethylene glycol) copolymer having a poly(ethyleneglycol) structure portion with a weight average molecular weight in arange from 2000 to 50000 can be preferably used. If the molecular weightis in this range, the embolization material becomes homogeneouslybiodegradable and it does not happen that the poly(ethylene glycol)produced from the copolymer degraded in vivo is unlikely to bedischarged outside the body. Furthermore, it is preferred that theweight average molecular weight of the poly(ethylene glycol) copolymeris in a range from 3000 to 100000.

It is preferred that the water insoluble poly(ethylene glycol) copolymeris a copolymer having a structure in which a poly(ethylene glycol)derivative (hereinafter called the block B) and a biodegradable polymer(hereinafter called the block A) are chemically bonded to each other.Furthermore, a copolymer having a structure in which the block A ischemically bonded to the hydroxyl groups of the block B is morepreferred. As for the block bonding types, the following structures canbe preferably used.

-   A copolymer in which a biodegradable polymer is chemically bonded to    the hydroxyl group at one end of poly(ethylene glycol) (A-B type    block copolymer)-   A copolymer in which a biodegradable polymer is chemically bonded to    the hydroxyl groups at both the ends of poly(ethylene glycol) (A-B-A    type block copolymer)-   A copolymer in which poly(ethylene glycol) and a biodegradable    polymer are alternately bonded to each other ((A-B)n type    multi-block copolymer)-   A multi-branched copolymer having a structure in which a    biodegradable polymer is chemically bonded to the three or more    hydroxyl groups of multi-branched poly(ethylene glycol) wherein a    compound with three or more hydroxyl groups such as glycerol,    polyglycerol, pentaerythritol or polypentaerythritol as a    poly(ethylene glycol) derivative and poly(ethylene glycol) are    chemically bonded to each other (An-B type block copolymer)

Furthermore, preferred is a copolymer in which the weight averagemolecular weight of the poly(ethylene glycol) derivative is from 2000 to50000 while the weight average molecular weight of the aforesaid blockcopolymer is from 3000 to 100000.

With regard to the A-B-A type block copolymer, A-B type block copolymer,An-B type block copolymer and (A-B)n type multi-block copolymer, if theaverage molecular weight is too small, the copolymer is likely to begelled, and when it is injected into a blood vessel, it can happen thatthe copolymer adheres to the catheter or the blood vessel, not allowingthe blood vessel to be blocked at the intended site. On the other hand,if the average molecular weight is too large, there may be such a casewhere it takes a long time for the material with a large averagemolecular weight to be degraded in vivo.

The average molecular weight of a water insoluble poly(ethylene glycol)copolymer can be measured by means of gel permeation chromatography(GPC).

In the examples of this invention, the following method was used.

-   Column: TSK gel XL series (inner diameter 7.8 mm, length 30 cm,    produced by Tosoh Corp.)-   Eluting solution: Chloroform-   Column temperature: 35° C.-   Flow velocity: 1.0 ml/min-   Detection method: Refractive index (RI8010 Refractometer: Produced    by Tosoh Corp.)-   Calibration curve: Prepared by using respective polystyrene standard    samples with average molecular weights of 1,110,000, 707,000,    397,000, 189,000, 98,900, 37,200, 17,100, 9490, 5,870, 2,500 and    1,050 and 500-   Data processing: Class Vp Data Analysis Workstation (produced by    Shimadzu Corp.)

In view of uniform degradability, it is preferred that the waterinsoluble poly(ethylene glycol) copolymer has such a narrow molecularweight distribution that the ratio of weight average molecular weight(Mw) to number average molecular weight (Mn), i.e., Mw/Mn of thecopolymer calculated from the peak measured by means of GPC is 2 orless.

With regard to the water insoluble poly(ethylene glycol) copolymer ofthis invention, a method for producing an A-B-A type block copolymer isexemplified below. Poly(ethylene glycol) is synthesized by polymerizingethylene oxide by a conventional method or obtained as a commerciallyavailable product. The average molecular weight of poly(ethylene glycol)is not especially limited, but as described above, a range from 2000 to50000 is preferred. As the poly(ethylene glycol) with a specifiedaverage molecular weight, products commercially available under tradenames of “Macrogol” (produced by Sanyo Chemical Industries, Ltd.) and“Sunbright” (produced by NOF Corp.) can be preferably used. In the casewhere a ring-opening polymerization method is used to synthesize fromethylene oxide, it is preferred that the molecular weight distributionof the synthesized poly(ethylene glycol) is narrow.

Next, the copolymerization between poly(ethylene glycol) (the block B)and a raw material (for example, a monomer such as lactic acid orglycolic acid, or cyclic dimer such as lactide or glycolide) of abiodegradable polymer (the block A) described later is performed usingan adequate catalyst described later. For example, in the case where ahydroxycarboxylic acid such as lactic acid or glycolic acid ispolymerized, a condensation polymerization method can be preferablyused, and in the case where a cyclic compound such as lactide orglycolide is polymerized, a ring-opening polymerization method can bepreferably used. The produced A-B-A type copolymer is purified by afractional precipitation method. That is, in the case where therespective structures of the block A and the block B exist respectivelyalone as polymers, the obtained A-B-A type copolymer is dissolved intoan organic solvent capable of dissolving the respective polymers(hereinafter such a solvent is called a good solvent). While thesolution is stirred, an organic solvent capable of dissolving either ofthe polymers but incapable of dissolving the other polymer (hereinaftersuch a solvent is called a poor solvent) is added dropwise into thepolymer having the structure of block A and the polymer having thestructure of block B, and the produced precipitate is taken out of thesystem. If this operation is repeated, a copolymer with a narrowmolecular weight distribution, i.e., an A-B-A type copolymer with asmall Mw/Mn ratio value can be produced.

After dropwise addition of a poor solvent, a precipitate is produced asa white turbid material. If the temperature of the white turbid materialis changed to once dissolve the precipitate and is again slowly returnedto the original temperature, to produce a precipitate, the fractionationaccuracy can also be raised.

The good solvent used in said fractional precipitation method can bedecided adequately depending on the polymers, and examples of it includetetrahydrofuran, halogen-based organic solvents (dichloromethane,chloroform), acetone, methanol and mixed solvents consisting of theforegoing.

The amount of the good solvent used depends on the added amounts of rawmaterials and the chemical composition of the copolymer. Usually theamount is from 1 to 50 wt % as the concentration in a copolymersolution. A preferred range is from 1 to 25 wt %.

The poor solvent used in said fractional precipitation method can beadequately decided depending on the polymers, but an alcohol-basedorganic solvent or a hydrocarbon-based organic solvent is preferred.

In said condensation polymerization method or ring-openingpolymerization method, a polymerization reactor with stirring blades ischarged with a poly(ethylene glycol) derivative with a predeterminedaverage molecular weight as a raw material and the raw material of abiodegradable polymer in dry air or in a dry nitrogen stream, andheated, and the mixture is stirred together with a catalyst, to obtainthe intended product. As another method, a vented double-screw kneadingextruder or an apparatus having similar stirring and feedinq functionsis used to stir, mix and degas the raw material of the biodegradablepolymer together with the catalyst, and the produced A-B-A typecopolymer is continuously taken out for accomplishment ofpolymerization.

The raw material of the biodegradable polymer is one or more selectedfrom the following examples of compounds.

-   a-hydroxy acids (for example, lactic acid, glycolic acid,    2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxycapric acid,    2-hydroxycaprylic acid, etc.), cyclic dimmers:of a-hydroxy acids    (forexample, lactide, glycolide, etc.), hydroxydicarboxylic acids    (for example, malic acid, etc.), cyclic esters such as trimethylene    carbonate, epsilon-caprolactone, 1,4-dioxanone, 1,4-dioxepane-7-one

Among the cyclic dimmers of a-hydroxy acids, lactide and glycolide arepreferred. Among the hydroxydicarboxylic acids, malic acid is preferred.In the case where two or more raw materials of biodegradable polymersare used, it is preferred to combine lactic acid (or lactide) andglycolic acid (or glycolide), and it is preferred that the ratio byweight of lactic acid to glycolic acid is from 100:0 to 50:50.Furthermore, in the case where two or more raw materials ofbiodegradable polymers are used, a combination consisting of lactic acid(or lactide) and epsilon-caprolactone is preferred, and it is preferredthat the ratio by weight of lactic acid to epsilon-caprolactone is from100:0 to 40:60. In the above, in the case of a compound optically activein the molecule such as lactic acid or lactide, any of D-form, L-form ora mixture consisting of D-form and L-form can be used.

With regard to preferred combinations constituting A-B type, A-B-A type,AnB type (n>3) or (A-B)n type copolymer, as the biodegradable block A,preferably used are poly(lactic acid), poly(lactic acid/glycolic acid,polylactide/glycolide), poly(lactic acid/epsilon-caprolactone),poly(lactide/epsilon-caprolactone), poly(glycolicacid/epsilon-caprolactone), poly(glycolide/epsilon-caprolactone),poly(lactic acid/trimethylene carbonate), poly(lactide/trimethylenecarbonate), poly(glycolic acid/trimethylene carbonate) andpoly(glycolide/trimethylene carbonate). Furthermore, for example, if apoly(ethylene glycol) polymer containing L-lactide structure and apoly(ethylene glycol) polymer containing D-lactide structure such as acombination consisting of poly(L-lactide)-PEG and poly(D-lactide)-PEGare blended to form a stereo complex, it can be preferably used, sinceit is excellent in thermal stability. In the above, “/” indicatescomonomers.

The catalyst used for polymerization is not especially limited if it isa catalyst used for ordinary polymerization for producing polyesters.Examples of the catalyst include tin halides such as tin chloride, tinsalts of organic acids such as tin 2-ethylhexanoate, organic tins suchas dibutyltin oxide, dibutyltin dichloride, dibutyltin dilaurate anddibutyltin maleate (polymer), etc. Other examples include organic alkalimetal compounds such as diethylzinc, zinc lactate, iron lactate,dimethylaluminum, calcium hydride and butyllithium, metal porphyrincomplex, metal alkoxides such as diethylaluminum methoxide, etc.

The water insoluble poly(ethylene glycol) copolymer has been explainedabove, and the embolization material containing it can further contain,as required, a polymer other than said ingredients to such an extentthat the effects of the invention are not impaired.

In this invention, in the case where the embolization material formed asparticles is used in actual therapy, it is preferred to use it as anembolizing agent with the particles dissolved in an aqueous liquid,preferably a physiologic saline. A femoral artery is punctured with adouble needle through the skin of the body, and subsequently the innerneedle is removed while the outer cylinder is allowed to indwell in thecavity of the blood vessel. Then, a guide wire is inserted into theblood vessel through it. Using it as an axis, a guiding catheter and amicrocatheter are inserted into the blood vessel. Observing an X-rayimage, the tip of the microcatheter is made to reach an intended bloodvessel of, for example, a hepatic artery, gastroduodenal artery,mesenteric artery, gastric artery, uterine artery, internal carotidartery, communicating artery, basilar artery, cerebral artery,cerebellar artery, etc., and subsequently, a syringe containing anembolizing agent with particles dispersed is attached to the catheterfor injection. A method of mixing an X-ray contrast medium with theembolizing agent to facilitate observation under fluoroscopy can bepreferably used.

The embolizing agent of this invention can be used as it is or asdispersed in an adequate dispersion medium or in a contrast medium suchas an iodine addition product obtained from poppy seed oil. As thecontrast medium, a publicly known one can be used, and either an ioniccontrast medium or a non-ionic contrast medium can be used. Particularexamples of it include “Iopamiron” (produced by Schering A G),“Hexabrix” (produced by Eiken Chemical Co., Ltd.), “Omnipaque” (producedby Daiichi Pharmaceutical Co., Ltd.), “Urografin” (produced by ScheringA G), “Iomeron (produced by Eisai Co., Ltd.), etc. The embolizing agentof this invention and a contrast medium can be mixed before use, and themixture can be injected into a predetermined site. If the water swellingcapability is high, the contrast medium is partly held inside theembolization material together with water, to express the contrasteffect. Examples of the dispersion medium include solutions with adispersing agent (for example, polyoxysorbitan fatty acid ester,carboxymethyl cellulose, etc.), preservative (for example,methylparaben, propylparaben, etc.), or isotonic agent (for example,sodium chloride, mannitol, glucose, etc.) dispersed in distilled waterfor injection, and vegetable oils such as sesame oil and corn oil. Thedispersed embolization material is administered from an adequate arteryinto a tumor-feeding artery using the inserted catheter while anangiographic agent is used for monitoring. Furthermore, an antiseptic,stabilizer, isotonic agent, solubilizing agent, dispersing agent,excipient, etc. usually added to an injection can also be added to theembolizing agent.

The embolizing agent of this invention can also be used together with anoily contrast medium such as an iodine addition product obtained frompoppy seed oil (Lipiodol Ultra-Fluid). Moreover, it can also be usedtogether with an iodine addition product obtained from poppy seed oiland an anticancer drug such as Smancs, neocarzinostatin, mitomycin-C,adriamycin, irinotecan hydrochloride, fluorouracil, epirubicinhydrochloride, cisplatin or vinblastine sulfate.

The embolization material of this invention can achieve the object ofthis invention, even if it does not contain a medicinally effectiveingredient. However, for the purpose of giving a further effect, it canalso contain a medicinally effective ingredient. The medicinallyeffective ingredient is not especially limited, if it has a knownmedicinal effect. Examples of the medicinally effective ingredientinclude anticancer drugs (for example, Smancs, neocarzinostatin,mitomycin-C, adriamycin, irinotecan hydrochloride, fluorouracil,epirubicin hydrochloride, cisplatin, paclitaxel, calcium leucovorin,vinblastine sulfate, altretamine, bleomycin, doxorubicin hydrochloride,Picibanil, Krestin, lentinan, cyclophosphamide, thiotepa, tegafur,vinblastine sulfate, pirarubicin hydrochloride), vascularizationinhibitors, steroid hormones, hepatic disease drugs, arthrifuges,antidiabetic agents, drugs for circulatory organs, hyperlipidemia drugs,bronchodilators, antiallergic drugs, drugs for digestive organs,antipsychotic drugs, chemical therapeutic agents, antioxidants,peptide-based drugs, protein-based drugs (for example, interferon), etc.

This invention is described below in further detail based on examples.

EXAMPLES Example 1

Under a nitrogen stream, 40.3 g of L-lactide (produced by Purac Biochem)and 17.3 g of dehydrated poly(ethylene glycol) with an average molecularweight of 20000 (produced by Sanyo Chemical Industries, Ltd.) weremolten and mixed at 140° C. in a flask, and 8.1 mg of tin dioctanoate(produced by WakoPure Chemical Industries, Ltd.) was added. Then, areaction was performed at 180° C., to obtain an A-B-A type copolymer(PLA-PEG-PLA). The obtained copolymer was dissolved into chloroform, andthe solution was added dropwise into a very excessive amount ofmethanol, to obtain a white precipitate. The weight average molecularweight by the GPC method was about 70000.

The aforesaid purified copolymer was dissolved into dichloromethane, andby the method of drying in an O/W emulsion, spherical particles wereobtained. The spherical particles were dried in vacuum, and fractionatedusing a nylon mesh. The fractionated particles were immersed in aphysiologic saline, to obtain a dispersion containing sphericalparticles. The particle size distribution was measured using “MICROTRACHRA-X100” produced by Leeds and Northrup, to obtain a volume averageparticle size of about 330 micrometer and a distribution width ofaverage particle size ±40 micrometer. The particle size was directlyobserved using an ultra depth shape measuring microscope, “VK-8500”produced by Keyence, and the water swelling ratios of ten particles witha diameter of about 330 micormeter immersed in purified water weremeasured, and a water swelling ratio of 130% was obtained.

Furthermore, a dichloromethane solution containing 5 wt % of theaforesaid purified copolymer was developed on a plate, to obtain anabout 30 micrometer thick cast film. The film was immersed in purifiedwater for 24 hours, and it was found to have a water content of 81%, anelastic modulus in tension of 184 MPa and a tensile elongation of 240%.Meanwhile, the elastic modulus in tension of the cast film in the drystate was 230 MPa.

At first, catheter passing capability was examined. The sphericalparticle dispersion was injected from a syringe into a catheter, MassTransit (overall length about 1400 mm, length of tip portion 180 mm,inner diameter of tip portion about 680 micrometer) produced by Cordis.It could be injected without any resistance. Furthermore, a small amountof a physiologic saline was injected, and subsequently the catheter wasdissected in the longitudinal direction to visually observe the insideof the catheter. No remaining spherical particle was observed at all.

Next, the blocking of a thin catheter used as a blood vessel model wasexamined. The spherical particle dispersion was injected from a syringeinto a catheter, Spinnaker 1.5F (overall length about 1650 mm, length oftip portion 150 mm, inner diameter of tip portion about 280 micrometer)produced by Boston Scientific. Immediately after start of injection, astrong resistance acted not to allow injection. No particle that passedthrough the tip portion could be seen.

From the above, it can be seen that particles with a uniform particlesize and made flexible due to water absorption and swelling passedthrough a microcatheter (catheter with an inner diameter of about 680micrometer) without causing cohesion or clogging, and on the other hand,that they could reliably block a fine catheter (catheter with an innerdiameter of about 280 micrometer) used as a blood vessel model.Furthermore, since the particles were swollen due to absorbed water,they were unlikely to injure the blood vessel and could be deformed inresponse to the form of the blood vessel, to allow perfect blocking.

Said spherical particles were added into a phosphate buffered saline (pH7.3) (produced by Nacalai Tesque, Inc.), and after lapse of 28 days at37° C, the remaining weight in comparison with the weight beforetreatment was obtained and found to be 75%.

Comparative Example 1

Under a nitrogen stream, 40.3 g of L-lactide (produced by Purac Biochem)and 8.1 mg of tin dioctanoate (produced by Wako Pure ChemicalIndustries, Ltd.) were added into a flask and a reaction was performedat 140° C. to obtain poly(L-lactide). The obtained polymer was dissolvedinto chloroform, and the solution was added dropwise into a veryexcessive amount of methanol, to obtain a white precipitate. The weightaverage molecular weight obtained by the GPC method was about 70000.

The obtained polymer was used to obtain a spherical particle dispersionof poly(L-lactide) by the same method as described for Example 1. Thevolume average particle size in a physiologic saline was about 300micrometer, and the distribution width was average particle size ±40micrometer. Furthermore, in the observation using a microscope, theparticle size of the particles saturated with water was not differentfrom that of the particles in the dry state, and a water swelling ratiowas found to be 0%.

Furthermore, a dichloromethane solution containing 5 wt % of theaforesaid purified copolymer was developed on a plate, to obtain anabout 30 micrometer thick cast film. The film was immersed in purifiedwater for 24 hours, and it was found to have a water content of 2%, anelastic modulus in tension of 1570 MPa and a tensile elongation of 4%.The elastic modulus in tension of the cast film in the dry state was1550 MPa.

The spherical particle dispersion of poly(L-lactide) was injected from asyringe into a catheter, Mass Transit (overall length about 1400 mm,length of tip portion 180 mm, inner diameter of tip portion about 680micrometer) produced by Cordis. Immediately after start of injection, astrong resistance acted not to allow injection. Some particles passedthrough the tip portion, but most of the particles could not passthrough the microcatheter.

Meanwhile, said spherical particles were added to the phosphate bufferedsaline (pH 7.3), and after lapse of 28 days at 37° C., the remainingweight in comparison with the weight before treatment was obtained andfound to be 98%.

The particles of the embolization material of this comparative examplecould not be swollen with water and did not contain a poly(ethyleneglycol) copolymer. So, probably because they were likely to adhere andcohere together in the catheter and blood vessel, even the particlessmaller than the inner diameter of the microcatheter could not passthrough the microcatheter.

Example 2

Under a nitrogen stream, 23.1 g of L-lactide, 9.1 g ofepsilon-caprolactone and 23.1 g of poly(ethylene glycol) (dehydrated)with an average molecular weight of 8000 were mixed in a flask, and themixture was molten and mixed at 140° C. Then, 8.1 mg of tin dioctanoatewas added to perform a reaction at 180° C., for obtaining an A-B typecopolymer {P(LA/CL)-PEG)}. The obtained copolymer was dissolved intochloroform, and the solution was added dropwise into a very excessiveamount of methanol, to obtain a white precipitate. The weight averagemolecular weight by the GPC method was about 22000.

The aforesaid purified copolymer was dissolved into dichloromethane, andthe method of drying in an OW emulsion was used to obtain sphericalparticles. The spherical particles were dried in vacuum and fractionatedusing a nylon mesh. The fractionated particles were immersed in aphysiologic saline to obtain a spherical particle dispersion. From theparticle side distribution measurement, it was found that the volumeaverage particle size was about 100 micrometer and that the distributionwidth was average particle size ±40 mm. The water swelling ratios of tenparticles with a diameter of about 100 micrometer immersed in purifiedwater were measured, and a water swelling ratio of 37% was obtained.

Furthermore, according to the same method as described for Example 1, afilm was obtained and found to have a water content of 40%, an elasticmodulus in tension of 47 MPa and a tensile elongation of 15%. Theelastic modulus in tension of the cast film in the dry state,was 200MPa.

A 24G indwelling needle was inserted into a femoral vein of each 10-weekold rat anesthetized with Nembutal, and subsequently a sphericalparticle dispersion with 60 mg of the particles dispersed in 1 mL of aphysiologic saline was injected. Two weeks later, the lungs wereobserved in appearance and tissue sections were prepared. The sphericalparticle dispersion was injected into four rats respectively and theirtissue sections were observed. In all the four rats, pulmonaryinfarction was observed.

Example 3

Under a nitrogen stream, 21.6 g of L-lactide (produced by PuracBiochem), 5.8 g of glycolide (produced by Purac Biochem) and 28.8 g ofdehydrated poly(ethylene glycol) with an average molecular weight of20000 (produced by Sanyo Chemical Industries, Ltd.) were mixed in aflask, and the mixture was dissolved and mixed at 140° C. Then, at 180°C., 8.1 mg of tin dioctanoate (produced by Wako Pure ChemicalIndustries, Ltd.) was added to perform a reaction for obtainingpoly(L-lactide/glycolide)-poly(ethyleneglycol)-poly(L-lactide/glycolide) copolymer. The copolymer was dissolvedinto chloroform and the solution was added dropwise into a veryexcessive amount of methanol, to obtain a white precipitate. The weightaverage molecular weight by the GPC method was 42000.

A dichloromethane solution containing 5 wt % of the obtained purifiedcopolymer was developed on a plate to obtain an about 30 micrometerthick cast film. The film was immersed in purified water for 24 hours,and it was found to have a water content of 215%, an elastic modulus intension of 7 MPa and a tensile elongation of 156%. The elastic modulusin tension of the cast film in the dry state was 200 MPa.

The aforesaid purified copolymer was dissolved into dichloromethane, andthe method of drying in an O/W emulsion was used to obtain sphericalparticles. The spherical particles were dried in vacuum and thenfractionated using a nylon mesh. The fractionated particles wereimmersed in a physiologic saline, to obtain a spherical particledispersion with a volume average particle size of 350 micrometer and adistribution width of average particle size ±40 micrometer. The waterswelling ratios of ten particles with a diameter of about 350 micrometerimmersed in purified water were measured, and a water swelling ratio of188% was obtained.

According to the same method as described for Example 1, a film wasobtained and found to have a water content of 215%, an elastic modulusin tension of 7 MPa and a tensile elongation of 156%. The elasticmodulus in tension of the cast film in the dry state was 200 MPa.

The aforesaid spherical particle dispersion was injected from a syringeinto a catheter, Mass Transit (overall length about 1400 mm, length oftip portion 180 mm, inner diameter of tip portion about 680 micrometer)produced by Cordis. It could be injected without any resistance.Subsequently, the catheter was dissected in the longitudinal directionand the inside of the catheter was visually observed. No remainingspherical particle was observed at all.

Next, the blocking of a thin catheter used as a blood vessel model wasexamined. The spherical particle dispersion was injected from a syringeinto a catheter, Spinnaker 1.5F (overall length about 1650 mm, length oftip portion 150 mm, inner diameter of tip portion about 280 micrometer)produced by Boston Scientific. Immediately after start of injection, astrong resistance acted not to allow injection. No particle that passedthrough the tip portion was observed.

Meanwhile, said spherical particles were added into the phosphatebuffered saline (pH 7.3), and after lapse of 28 days at 37° C., theremaining weight in comparison with the weight before treatment wasobtained and found to be 40%.

Moreover, said nylon mesh was used for fractionation, and a sphericalparticle dispersion with a volume average particle size of about 90micrometer and a particle size distribution width of ±50 micrometer in aphysiologic saline was obtained. Then, a 24G indwelling needle wasinserted into a femoral vein of each 10-week old rat anesthetized withNembutal, and a spherical particle dispersion with 60 mg of theparticles dispersed in 1 mL of a physiologic saline was injected. Twoweeks later, the lungs were observed in appearance, and tissue sectionswere prepared. The spherical particle dispersion was injected into fourrats respectively, and the tissue sections were observed. In all thefour rats, pulmonary infarction was observed.

Example 4

Under a nitrogen stream, 19.2 g of L-lactide (produced by PuracBiochem), 9.6 g of glycolide (produced by Purac Biochem) and 28.8 g ofdehydrated methoxy poly(ethylene glycol) with an average molecularweight of 20000 (produced by Sanyo Chemical Industries, Ltd.) were mixedin a flask, and the mixture was dissolved and mixed at 140° C. Then, 8.1mg of tin dioctanoate (produced by Wako Pure Chemical Industries, Ltd.)was added at 180° C. to perform a reaction, for obtainingpoly(L-lactide/glycolide)-poly(ethylene glycol) copolymer. The copolymerwas dissolved into chloroform, and the solution was added dropwise intoa very excessive amount of methanol, to obtain a white precipitate. Theweight average molecular weight by the GPC method was 48000.

A dichloromethane solution containing 5 wt % of the obtained purifiedcopolymer was developed on a plate, to obtain an about 30 micrometerthick cast film. The film was immersed in purified water for 24 hours,and it was found to have a water content of 310%, an elastic modulus intension of 6 MPa and a tensile elongation of 9%. The elastic modulus intension of the cast film in the dry state was 380 MPa.

The aforesaid purified copolymer was dissolved into dichloromethane, andthe method of drying in an O/W emulsion was used to obtain sphericalparticles. The spherical particles were dried in vacuum and thenfractionated using a nylon mesh. The fractionated particles wereimmersed in a physiologic saline, to obtain a spherical particledispersion with a volume average particle size of 360 mm and adistribution width of average particle size ±30 micrometer. The waterswelling ratios of ten particles with a diameter of about 360 micrometerimmersed in purified water were measured, and a water swelling ratio of246% was obtained.

The aforesaid spherical particle dispersion was injected from a syringeinto a catheter, Mass Transit (overall length about 1400 mm, length oftip portion 180 mm, inner diameter of tip portion about 680 micrometer)produced by Cordis. It could be injected without any resistance.Subsequently, the catheter was dissected in the longitudinal direction,and the inside of the catheter was visually observed. No remainingspherical particle was observed at all.

Next, the blocking of a thin catheter used as a blood vessel model wasexamined. The spherical particle dispersion was injected from a syringeinto a catheter, Spinnaker 1. 5F (overall length about 1650 mm, lengthof tip portion 150 mm, inner diameter of tip portion about 280micrometer) produced by Boston Scientific, and immediately after startof injection, a strong resistance acted not to allow injection. Noparticle that passed through the tip portion was observed.

Meanwhile, said spherical particles were added into the phosphatebuffered saline (pH 7.3), and after lapse of 28 days at 37° C., theremaining weight in comparison with the weight before treatment wasobtained and found to be 35%.

Example 5

Under a nitrogen stream, 23.1 g of D,L-lactide (produced by PuracBiochem), 11.5 g of glycolide (produced by Purac Biochem) and 23.1 g ofa dehydrated tetra-branched poly(ethylene glycol) derivative with anaverage molecular weight of 20000, “Sunbright PTE-20000” (produced byNOF Corp.) were mixed in a flask, and the mixture was dissolved andmixed at 140° C. Then, 8.1 mg of tin dioctanoate (produced by Wako PureChemical Industries, Ltd.) was added at 180° C. to perform a reactionfor obtaining poly(D,L-lactide/glycolide)x4-poly(ethylene glycol)copolymer. The copolymer was dissolved into chloroform, and the solutionwas added dropwise into a very excessive amount of methanol, to obtain aprecipitate. The weight average molecular weight by the GPC method was62000.

A dichloromethane solution containing 5 wt % of the obtained purifiedcopolymer was developed on a plate, to obtain an about 30 micrometerthick cast film. The film was immersed in purified water for 24 hours,and it was found to have a water content of 330%, an elastic modulus intension of 4 MPa and a tensile elongation of 45%. Meanwhile, the elasticmodulus in tension of the cast film in the dry state was 25 MPa.

The aforesaid purified copolymer was dissolved into dichloromethane, andthe method of drying in an O/W emulsion was used to obtain sphericalparticles. The spherical particles were dried in vacuum and thenfractionated using a nylon mesh. The fractionated particles wereimmersed into a physiologic saline, to obtain a spherical particledispersion with a volume average particle size of 360 micrometer and adistribution width of average particle size ±40 micrometer. The waterswelling ratios of ten particles with a diameter of about 350 micrometerimmersed in purified water were measured, and a water swelling ratio of251% was obtained.

The aforesaid spherical particle dispersion was injected from a syringeinto a catheter, Mass Transit (overall length about 1400 mm, length oftip portion 180 mm, inner diameter of tip portion about 680 micrometer)produced by Cordis. It could be injected without any resistance.Subsequently, the catheter was dissected in the longitudinal direction,and the inside of the catheter was visually observed. No remainingspherical particle was observed at all.

Next, the blocking of a fine catheter used as a blood vessel modelwasexamined. The spherical particle dispersion was injected from a syringeinto a catheter, Spinnaker 1.5F (overall length about 1650 mm, length oftip portion 150 mm, inner diameter of tip portion about 280 micrometer)produced by Boston Scientific, and immediately after start of injection,a strong resistance acted not to allow injection. No particle thatpassed through the tip portion was observed.

Meanwhile, said spherical particles were added into the phosphatebuffered saline (pH 7.3), and after lapse of 28 days at 37° C., theremaining weight in comparison with the weight before treatment wasobtained and found to be 40%.

Example 6

Under a nitrogen stream, 34.6 g of L-lactide (produced by Purac Biochem)and 23.1 g of a dehydrated octa-branched poly(ethylene glycol)derivative with an average molecular weight of 20000, “SunbrightHGEO-20000” (produced by NOF Corp.) were mixed in a flask, and themixture was dissolved and mixed at 140° C. Then, 8.1 mg of tindioctanoate (produced by Wako Pure Chemical Industries, Ltd.) was addedat 180° C., to perform a reaction, for obtaining a copolymer L with astructure of poly(L-lactide)x8-poly(ethylene glycol). The copolymer wasdissolved into chloroform, and the solution was added dropwise into avery excessive amount of methanol, to obtain a white precipitate. Theweight average molecular weight by the GPC method was 65000.

Under a nitrogen stream, 34.6 g of D-lactide (produced by Purac Biochem)and 23.1 g of a dehydrated octa-branched poly(ethylene glycol)derivative with an average molecular weight of 20000, “SunbrightHGEO-20000” (produced by NOF Corp.) were mixed in a flask, and themixture was dissolved and mixed at 140° C. Then, 8.1 mg of tindioctanoate (produced by Wako Pure Chemical Industries, Ltd.) was addedat 180° C, to perform a reaction, for obtaining a copolymer D with astructure of poly(D-lactide)x8-poly(ethylene glycol). The copolymer wasdissolved into chloroform, and the solution was added dropwise into avery excessive amount of methanol, to obtain a white precipitate. Theweight average molecular weight by the GPC method was 65000.

A dichloromethane solution containing 5 wt % of the purified copolymer Land a dichloromethane solution containing 5 wt % of the purifiedcopolymer D were mixed at a ratio by weight of 1:1 to obtain a blendedsolution, and it was developed on a plate, to obtain an about 30micrometer thick cast film. The thermal properties of the cast film weremeasured using a differential scanning calorimeter, “DSC6200” producedby Seiko Instruments Inc. The melting peak attributable to thepoly(L-lactide) of the copolymer L was 148° C., and the melting peakattributable to the poly(D-lactide) of the copolymer D was 148° C. Onthe contrary, the melting peak attributable to the blend consisting ofthe copolymer L and the copolymer D was 198° C., about 50° C. higher,and no peak was observed at 148° C. From the results, it was judged thatthe blend formed a stereo complex. The film was immersed in purifiedwater for 24 hours, and it was found to have a water content of 123%, anelastic modulus in tension of 21 MPa and a tensile elongation of 12%.The elastic modulus in tension of the cast film in the dry state was 100MPa.

The aforesaid purified copolymer was dissolved into dichloromethane, andthe method of drying in an O/W emulsion was used to obtain sphericalparticles. The spherical particles were dried in vacuum and thenfractionated using a nylon mesh. The fractionated particles wereimmersed in a physiologic saline, to obtain a spherical particledispersion with a volume average particle size of 340 micrometer and adistribution width of average particle size ±40 micrometer. The waterswelling ratios of ten particles with a diameter of about 340 mmimmersed in purified water were measured, and a water swelling ratio of152% was obtained.

The aforesaid spherical particle dispersion was injected from a syringeinto a catheter, Mass Transit (overall length about 1400 mm, length oftip portion 180 mm, inner diameter of tip portion about 680 micrometer)produced by Cordis. It could be injected without any resistance.Subsequently, the catheter was dissected in the longitudinal direction,and the inside of the catheter was visually observed. No remainingspherical particle could be observed at all.

Next, the blocking of a fine catheter used as a blood vessel model wasexamined. The spherical particle dispersion was injected from a syringeinto a catheter, Spinnaker 1.5F (overall length about 1650 mm, length oftip portion 150 mm, inner diameter of tip portion about 280 micormeter)produced by Boston Scientific, and immediately after start of injection,a strong resistance acted not to allow injection. No particle thatpassed through the tip portion was observed.

Meanwhile, said spherical particles were added into the phosphatebuffered saline (pH 7.3), and after lapse of 28 days at 37° C., theremaining weight in comparison with the weight before treatment wasobtained and found to be 43%.

Example 7

Under a nitrogen stream, 30.3 g of L-lactide (produced by PuracBiochem), 10.0 g of glycolide (produced by Purac Biochem) and 17.3 g ofdehydrated poly(ethylene glycol) with an average molecular weight of20000 (produced by Sanyo Chemical Industries, Ltd.) were mixed in aflask, and the mixture was dissolved and mixed at 140° C. Then, 8.1 mgof tin dioctanoate (produced by Wako Pure Chemical Industries, Ltd.) wasadded at 180° C, to perform a reaction, for obtainingpoly(lactide/glycolide)-poly(ethylene glycol)-poly(lactide/glycolide)copolymer. The copolymer was dissolved into chloroform, and the solutionwas added dropwise into a very excessive amount of methanol, to obtain awhite precipitate. The weight average molecular weight by the GPC methodwas 72000.

The obtained purified copolymer and the purified copolymer obtained inExample 4 were mixed at a ratio by weight of 9:1, and a dichloromethanesolution containing 5 wt % of the mixture was developed on a plate, toobtain an about 30 mm thick cast film. The film was immersed in purifiedwater for 24 hours, and it was found to have a water content of 223%, anelastic modulus in tension of 40 MPa and a tensile elongation of 100%.Meanwhile, the elastic modulus in tension of the cast film in the drystate was 90 MPa.

The aforesaid copolymer mixture was dissolved into dichloromethane, andthe method of drying in an OW emulsion was used to obtain sphericalparticles. The spherical particles were dried in-vacuum, and thenfractionated using a nylon mesh. The fractionated particles wereimmersed into a physiologic saline to obtain a spherical particledispersion with a volume average particle size of 350 micrometer and adistribution width of average particle size ±40 mm. The water swellingratios of ten particles with a diameter of about 350 micrometer immersedin pure water were measured, and a water swelling ratio of 210% wasobtained.

The aforesaid spherical particle dispersion was injected from a syringeinto a catheter, Mass Transit (overall length about 1400 mm, length oftip portion 180 mm, inner diameter of tip portion about 680 mm) producedby Cordis. It could be injected without any resistance. Subsequently,the catheter was dissected in the longitudinal direction, and the insideof the catheter was visually observed. No remaining spherical particlecould be observed at all.

Next, the blocking of a thin catheter used as a blood vessel model wasexamined. The spherical particle dispersion was injected from a syringeinto a catheter, Spinnaker 1.5F (overall length about 1650 mm, length oftip portion 150 mm, inner diameter of tip portion about 280 miicrometer)produced by Boston Scientific, and immediately after start of injection,a strong resistance acted not to allow injection. No particle thatpassed through the tip portion was observed.

Meanwhile, said spherical particles were added into the phosphatebuffered solution (pH 7.3), and after lapse of 28 days at 37° C., theremaining weight in comparison with the weight before treatment wasobtained and found to be 55%.

INDUSTRIAL APPLICABILITY

As described above, the embolization material of this invention canreliably block a blood vessel at an intended site without causingaggregation or clogging in a catheter or in the blood vessel at otherthan the intended site. Furthermore, irrespective of the blocking siteand the blocking environment, the blocked site concerned can beliberated from the embolized state with the lapse of time, and theembolization material is degraded finally in vivo. The degradedcomponents can be metabolized or excreted outside the body. Therefore,it can be suitably used in the field of medical therapy, as a hemorrhagepreventing means for a surgical operation, as arterial embolization tostop the supply of nutrition to a tumor incapable of being excised, andas chemo embolization therapy in which the anticancer drug concentrationin a tumor can be kept high.

1. An embolization material that has a water swelling ratio of 30% ormore and is formed as particles containing a synthetic polymer, beingdegradable in a phosphate buffered saline of 37° C.
 2. An embolizationmaterial, according to claim 1, wherein the synthetic polymer is a waterinsoluble poly(ethylene glycol) copolymer.
 3. An embolization material,according to claim 2, which has a water swelling ratio of 100% or more.4. An embolization material, according to claim 3, which is formed asvirtually spherical particles at 37° C.
 5. An embolization material,according to claim 4, which has a particle size distribution width in arange of average particle size ±micrometer.
 6. An embolization material,according to claim 1, wherein the remaining mass after it is immersed ina phosphate buffered saline of 37° C. for 28 days is 80% or less of theweight of it not yet immersed.
 7. An embolization material that has awater swelling ratio of 30% or more and is degradable in a phosphatebuffered saline of 37° C., being formed as virtually spherical particleswith an average particle size of 50 μm or more.
 8. An embolizationmaterial, according to claim 7, which contains a water insolublepoly(ethylene glycol) copolymer.
 9. An embolization material, accordingto claim 8, which has a water swelling ratio of 100% or more.
 10. Anembolization material, according to claim 9, wherein the remaining massafter it is immersed in a phosphate buffered saline of 37° C. for 28days is 80% or less of the weight of it not yet immersed.
 11. Anembolization material that is composed of a water insoluble polymer, inwhich when the film formed from the water insoluble polymer is saturatedwith water, it has an elastic modulus in tension of 1500 MPa or less.12. An embolization material, according to claim 11, wherein the filmsaturated with water has an elastic modulus in tension of 4 to 400 MPa.13. An embolization material, according to claim 12, wherein the elasticmodulus in tension of the film saturated with water is 60% or less ofthe elastic modulus in tension of the film in the dry state.
 14. Anembolization material, according to claim 13, wherein the film saturatedwith water has a tensile elongation of 100% or more.
 15. An embolizationmaterial, according to claim 14, which has a water swelling ratio of100% or more.
 16. An embolization material, according to claim 15,wherein the remaining mass of the water insoluble polymer after it isimmersed in a phosphate buffered saline of 37° C. for 28 hours is 80% orless of the weight of it not yet immersed.
 17. An embolization material,according to claim 16, wherein the water insoluble polymer is a blockcopolymer with a structure in which the structure of a biodegradablepolymer and the structure of a water soluble polymer are chemicallybonded to each other.
 18. An embolization material, according to claim16, wherein the water insoluble polymer is a poly(ethylene glycol)copolymer.
 19. An embolization material comprising a water insolublepoly(ethylene glycol) copolymer.
 20. An embolization material, accordingto claim 19, wherein the water insoluble poly(ethylene glycol) copolymeris a copolymer with a structure in which a poly(ethylene glycol)derivative and a biodegradable polymer are chemically bonded to eachother.
 21. An embolization material, according to claim 19, wherein thewater insoluble poly(ethylene glycol) copolymer is a copolymer with astructure in which a biodegradable polymer is chemically bonded to thehydroxyl groups of a poly(ethylene glycol) derivative.
 22. Anembolization material, according to claim 20, wherein the waterinsoluble poly(ethylene glycol) copolymer is a mixture consisting of apoly(ethylene glycol) copolymer containing a polymer synthesized fromL-lactic acid or L-lactide as the structure of the biodegradable polymerand a poly(ethylene glycol) copolymer containing a polymer synthesizedfrom D-lactic acid or D-lactide as the structure of the biodegradablepolymer.
 23. An embolization material, according to claim 20, whereinthe poly(ethylene glycol) derivative as a component of the waterinsoluble poly(ethylene glycol) polymer has a structure in which acompound having three or more hydroxyl groups and poly(ethylene glycol)are chemically bonded to each other.
 24. An embolization material,according to claim 21, wherein the water insoluble poly(ethylene glycol)copolymer has a weight average molecular weight of 3000 to 100000, andthe structure of the poly(ethylene glycol) derivative existing in thepoly(ethylene glycol) copolymer has a weight average molecular weight of2000 to
 50000. 25. An embolization material, according to claim 21,which has a water swelling ratio of 100% or more.
 26. An embolizationmaterial, according to claim 21, which is formed as particles at 37° C.27. An embolization material, according to claim 26, which has anaverage particle size of 50 to 2000 micrometer.
 28. An embolizationmaterial, according to claim 26, which has a particle size distributionwidth in a range of average particle size ±100 micrometer.
 29. Anembolization material, according to claim 26, which is formed asvirtually spherical particles at 37° C.
 30. An embolization material,according to claim 25, wherein the remaining mass after it is immersedin a phosphate buffered saline of 37° C. for 28 days is 80 wt % or lessof the weight of it not yet immersed.
 31. An embolization material,according to claim 25, which can be swollen with at least any one ofpurified water, physiologic saline and water soluble X-ray contrastmedium.
 32. An embolization material, according to claim 25, whichfurther holds a water soluble X-ray contrast medium in it.
 33. Anembolization material, according to claim 25, which has flexibility ofbeing deformed in response to the form of the blood vessel at the timeof embolization for allowing the blood flow to be stopped.
 34. Anembolization material, that contains a synthetic polymer, has a waterswelling ratio of 30% or more, is degradable in a phosphate bufferedsaline of 37° C., and is formed as virtually spherical particles with anaverage particle size of 50 micrometer or more, wherein the syntheticpolymer is a water insoluble poly(ethylene glycol) copolymer and thefilm formed from the synthetic polymer and saturated with water has anelastic modulus in tension of 1500 MPa or less.
 35. An embolizing agent,having the embolization material as in claim 1 dispersed in aphysiologic saline.
 36. An embolization method, comprising the steps ofinserting a catheter percutaneously into a blood vessel of an body, tolet its tip reach the site to be blocked, and injecting a solutioncontaining the embolization material as in claim 1 through the catheterinto the site to be blocked, for blocking the blood vessel.
 37. Anembolizing agent, having the embolization material as in claim 7dispersed in a physiologic saline.
 38. An embolizing agent, having theembolization material as in claim 11 dispersed in a physiologic saline.39. An embolizing agent, having the embolization material as in claim 19dispersed in a physiologic saline.
 40. An embolizing agent, having theembolization material as in claim 34 dispersed in a physiologic saline.41. An embolization method, comprising the steps of inserting a catheterpercutaneously into a blood vessel of an body, to let its tip reach thesite to be blocked, and injecting a solution containing the embolizationmaterial as in claim 7 through the catheter into the site to be blocked,for blocking the blood vessel.
 42. An embolization method, comprisingthe steps of inserting a catheter percutaneously into a blood vessel ofan body, to let its tip reach the site to be blocked, and injecting asolution containing the embolization material as in claim 11 through thecatheter into the site to be blocked, for blocking the blood vessel. 43.An embolization method, comprising the steps of inserting a catheterpercutaneously into a blood vessel of an body, to let its tip reach thesite to be blocked, and injecting a solution containing the embolizationmaterial as in claim 19 through the catheter into the site to beblocked, for blocking the blood vessel.
 44. An embolization method,comprising the steps of inserting a catheter percutaneously into a bloodvessel of an body, to let its tip reach the site to be blocked, andinjecting a solution containing the embolization material as in claim 34through the catheter into the site to be blocked, for blocking the bloodvessel.